Whole-exome sequencing identifies causative mutations in families with congenital anomalies of the kidney and urinary tract

Van Der Ven AT, Connaughton DM, Ityel H, Mann N, Nakayama M, Chen J, Vivante A, Hwang DY, Schulz J, Braun DA, Schmidt JM, Schapiro D, Schneider R, Warejko JK, Daga A, Majmundar AJ, Tan W, Jobst-Schwan T, Hermle T, Widmeier E, Ashraf S, Amar A, Hoogstraaten CA, Hugo H, Kitzler TM, Kause F, Kolvenbach CM, Dai R, Spaneas L, Amann K, Stein DR, Baum MA, Somers MJG, Rodig NM, Ferguson MA, Traum AZ, Daouk GH, Bogdanovic R, Stajic N, Soliman NA, Kari JA, El Desoky S, Fathy HM, Milosevic D, Al-Saffar M, Awad HS, Eid LA, Selvin A, Senguttuvan P, Sanna-Cherchi S, Rehm HL, Macarthur DG, Lek M, Laricchia KM, Wilson MW, Mane SM, Lifton RP, Lee RS, Bauer SB, Lu W, Reutter HM, Tasic V, Shril S, Hildebrandt F (2018)

Publication Type: Journal article

Publication year: 2018

Journal

Book Volume: 29

Pages Range: 2348-2361

Journal Issue: 9

DOI: 10.1681/ASN.2017121265

Abstract

Background Congenital anomalies of the kidney and urinary tract (CAKUT) are the most prevalent cause of kidney disease in the first three decades of life. Previous gene panel studies showed monogenic causation in up to 12% of patients with CAKUT. Methods We applied whole-exome sequencing to analyze the genotypes of individuals from 232 families with CAKUT, evaluating for mutations in single genes known to cause human CAKUT and genes known to cause CAKUT in mice. In consanguineous or multiplex families, we additionally performed a search for novel monogenic causes of CAKUT. Results In 29 families (13%), we detected a causative mutation in a known gene for isolated or syndromic CAKUT that sufficiently explained the patient's CAKUT phenotype. In three families (1%), we detected a mutation in a gene reported to cause a phenocopy of CAKUT. In 15 of 155 families with isolated CAKUT, we detected deleterious mutations in syndromic CAKUT genes. Our additional search for novel monogenic causes of CAKUT in consanguineous and multiplex families revealed a potential single, novel monogenic CAKUT gene in 19 of 232 families (8%). Conclusions We identified monogenic mutations in a known human CAKUT gene or CAKUT phenocopy gene as the cause of disease in 14% of the CAKUT families in this study. Whole-exome sequencing provides an etiologic diagnosis in a high fraction of patients with CAKUT and will provide a new basis for the mechanistic understanding of CAKUT.

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Involved external institutions

Harvard University United States (USA) (US) King Abdulaziz University (KAU) / جامعة الملك عبد العزيز Saudi Arabia (SA) Institute for Mother and Child Health Care Serbia (RS) Yale University United States (USA) (US) Dubai Hospital United Arab Emirates (AE) Boston Children's Hospital United States (USA) (US) Cairo University Egypt (EG) Alexandria University / جامعة الإسكندرية‎‎ Egypt (EG) Eli and Edythe L. Broad Institute of MIT and Harvard United States (USA) (US) Tamil Nadu Dr. M.G.R. Medical University (TNMGRMU) / தமிழ்நாடு டாக்டர் எம்.ஜி.ஆர். மருத்துவப் பல்கலைக்கழகம் India (IN) Saints Cyril and Methodius University of Skopje / Универзитет „Св. Кирил и Методиј“ во Скопје Republic of North Macedonia (MK) Boston University United States (USA) (US) Dr. Mehta's Hospital India (IN) Rheinische Friedrich-Wilhelms-Universität Bonn Germany (DE) Massachusetts General Hospital United States (USA) (US) University of Zagreb / Sveučilište u Zagrebu Croatia (HR) Columbia University United States (USA) (US)

How to cite

APA:

Van Der Ven, A.T., Connaughton, D.M., Ityel, H., Mann, N., Nakayama, M., Chen, J.,... Hildebrandt, F. (2018). Whole-exome sequencing identifies causative mutations in families with congenital anomalies of the kidney and urinary tract. Journal of the American Society of Nephrology, 29(9), 2348-2361. https://doi.org/10.1681/ASN.2017121265

MLA:

Van Der Ven, Amelie T., et al. "Whole-exome sequencing identifies causative mutations in families with congenital anomalies of the kidney and urinary tract." Journal of the American Society of Nephrology 29.9 (2018): 2348-2361.

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